JP2542225B2 - Esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one and related compounds - Google Patents

Description

The present invention relates to hexahydro-8-hydroxy-2,6-methano-2H-quinolidin-3 (4H) -one and hexahydro-8-hydroxy-2,6-. It relates to esters of methano-2H-quinolidine with certain aromatic and heterocyclic carboxylic acids. The invention also relates to a novel process for the preparation of the esters of the invention.

More specifically, the present invention provides the formula [Wherein A is = H ₂ , = O, = (H) (OH), = (OH) ₂ or = N-OH, and B is = H ₂ , = (H) (CH ₃ ), =
(H) (CH ₂ NR ₃ R ₄ ) or = CH ₂ , where R ₃ and R ₄ are C
_2-4 alkyl, or together are the the tetramethylene, pentamethylene or _{-CH 2 CH 2 -O-CH 2} CH 2 - cause, R ₁ is Wherein Z is NR ₉ , O or S, and R ₅ , R ₆ and R ₈ are hydrogen, halogen, C _1-3 alkyl or C _1-3 , respectively.
Alkoxy, R ₇ is hydrogen, amino, (C _1-4 alkyl) amino, (C _1-4 alkyl) ₂ amino, alkoxy or nitro, R ₉ is hydrogen, C _1-4 alkyl or phenyl (C _1-2 alkyl) and R ₁₀ is hydrogen, halogen, C _1-4
Alkyl, C _1-4 alkoxy, hydroxy, cyano, or
-CONH ₂ , R ₁₁ is hydrogen, halogen, C _1-4 alkyl or phenyl, and the wavy line indicates that the configuration of the oxygen substituent on the ring may be endo or exo],
Or, it relates to pharmaceutically acceptable acid addition salts and quaternary ammonium salts of the above compounds.

Examples of C _1-4 alkyl groups mentioned above are methyl, ethyl, propyl, isopropyl and butyl. Examples of C _1-4 alkoxy are methoxy, ethoxy, propoxy and butoxy. The above-mentioned halogens can be fluorine, chlorine or bromine. When the wavy line in the general structural formula changes to a solid line, this indicates that the configuration of the compound is the end. Such an endo compound can also be called trans. Similarly, exo compounds can be referred to as cis. Any hydrate of the compounds is considered equivalent to the compound itself, which includes compounds where the carbonyl (ie A is O) is present as (OH) ₂ .

A preferred group of compounds are those in which the ester is attached to the polycyclic ring in the endo configuration. A more preferred group are those with endo configurations where A is = O and = (0H) ₂ . In a more preferred group, B additionally =
It is H _2.

The above-mentioned pharmaceutically acceptable acid addition salts are with inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid or acetic acid; or organic carboxylic acids, such as acetic acid, propionic acid, glycolic acid, maleic acid, Hydroxymaleic acid, malic acid, tartaric acid, citric acid, salicylic acid,
2-acetyloxybenzoic acid, nicotinic acid or isonicotinic acid; or organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, 4-toluenesulfonic acid, or 2-naphthalenesulfonic acid It can be a non-toxic salt with a suitable acid, such as with an acid. Quaternary ammonium salts are formed with alkyl halides such as methyl chloride, methyl bromide or ethyl bromide; or with sulfuric acid esters such as methyl 4-toluenesulfonate and methyl 2-naphthalenesulfonate.

Some specific examples of compounds included in the present invention are as follows.

End-8- (3,5-dimethylbenzoxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H)-
On, exo-8- (3,5-dimethylbenzoyloxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H)-
On, endo-8- (3,5-dichlorobenzoyloxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H)-
On, endo-8- (3,5-dimethoxybenzoyloxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H)
-One, endo-8- (4-aminobenzoyloxy) hexahydro-2,6-methano-2H-quinolidin-3 (4H) -one, endo-8- (4-dimethylaminobenzoyloxy)
Hexahydro-2,6-methano-2H-quinolizine-3 (4
H) -one, endo-8- (3,5-dimethylbenzoyloxy) octahydro-2,6-methano-2H-quinolizine, endo-8- (3-indolylcarbonyloxy) octahydro-2,6- Methano-2H-quinolizine, endo-8- (5-cyano-3-indolylcarbonyloxy) hexahydro-2,6-methano-2H-quinolidin-3 (4H) -one, endo-8- (3,5 -Dichlorobenzoyloxy) hexahydro-2,6-methano-4-methyl-2H-quinolidin-3 (4H) -one, endo-8- (3-indolylcarbonyloxy) hexahydro-4- (diethylaminomethyl) -2,6-Methano-2H-quinolizin-3 (4H) -one, endo-8- (3-indolylcarbonyloxy) -3
-Hydroxyimino-2,6-methanooctahydro-2H-
Quinolidine, endo-8- (2-methyl-1-isoindolylcarbonyloxy) hexahydro-2,6-methano-2H-quinolidin-3 (4H) -one, endo-8- (2-pyrrolidinylcarbo Nyloxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H)
-One, and endo-8- (3-indolylcarbonyloxy) -2,
6-Methanooctahydro-2H-quinolidin-3-ol.

The compounds of the present invention have the formula Alcohol or reactive derivative thereof with [in A 'is formula = O or = H _2], wherein R ₁ COOH [wherein R ₁ is as defined above] and their equivalents reactive with acid It is made by reacting. By reactive equivalent is meant the corresponding acid chloride or bromide, or the corresponding glyoxylyl chloride or bromide, or the carboxylic acid imidazole obtained by reaction of the appropriate acid halide with N, N-carbonyldiimidazole. Or any similar acid derivative which upon reaction with an alcohol or a reactive derivative of an alcohol yields a simple carboxylic acid ester. More specifically, if the -OH of the alcohol is in the equatorial (exo), it can be reacted with the appropriate carboxylic acid imidazole obtained from the reaction of the acid halide with the N, N-carbonyldiimidazole. Instead, the acid is converted to the acid chloride by standard procedures (eg, thionyl chloride) and then the lithium salt, such as the lithium salt obtained by reaction of the alcohol with lithium or with lithium hydride in tetrahydrofuran.
React with alkali metal salts of alcohol.

-OH group in the starting alcohol is axial (end)
When this is present, it can also be converted to the corresponding ester by reaction with the appropriate acid chloride or bromide. The reaction is 4-
It is carried out in a high boiling inert solvent such as xylene in the presence of one equivalent of a suitable tertiary base such as dimethylaminopyridine. However, this procedure is not suitable for acid halides that are not stable under the specified conditions, as long heating (24-84 hours) above 140 ° C is required in this case. Therefore, alternative methods must be used to prepare such compounds. In this procedure, the appropriate acid chloride or bromide, or glyoxylyl chloride or bromide, in a nitroparaffin solvent is added to the alcohol superacid and 1
React with an equivalent amount of a solution of the same super acid heavy metal salt. Glyoxylyl chloride is readily decarbonylated under the conditions of use and can be used in the process as indicated. The reaction itself can be carried out at temperatures ranging from -80 ° C to ambient temperature (about 23 ° C) for 1-24 hours. Examples of suitable superacids at M = H are MBF ₄ , MAsF ₆ , MSbF ₆ , MPF ₆ , MTaF ₆ or MNbF ₆ , and examples of suitable heavy metals (M) are silver and thallium.
Examples of nitroparaffin solvents are nitromethane, nitroethane, 1-nitropropane and 2-nitropropane.

In fact, when R ₁ contains a primary or secondary amino group,
It is usually protected during the above reaction, a benzyl group is commonly used to protect secondary amines, and a benzyloxycarbonyl group is used to protect primary amines. In each case, the protecting groups in the product are removed by conventional procedures, for example hydrogenation with hydrogen and a palladium catalyst.

Various procedures can be used to convert the compounds, where A is = O, prepared as described below, to other different bridged derivatives of the invention by standard methods. Thus, a polycyclic ketone group can be reduced to the corresponding alcohol using an alkali metal (sodium or potassium) borohydride in a lower alkanol such as methanol or ethanol.

Ketone groups can also be completely reduced to methylene groups by a two-step procedure. Reaction of the ketone with ethylenedithiol or trimethylenedithiol in the presence of a strong acid such as hydrochloric acid or BF ₃ in the first step yields the corresponding dithioketal. The reaction is performed in a suitable polar solvent such as nitromethane or acetic acid. The dithioketal is then reduced with hydrazine in the presence of Raney nickel in a lower alkanol solvent such as 2-propanol at elevated temperature (60-100 ° C). In fact, using this same procedure, the original starting alcohol hexahydro-8-hydroxy-2,6-methano-2H-quinolidin-3 (4H) -one was converted to 8-hydroxy-
It can be reduced to 2,6-methanooctahydro-2H-quinolizine, which when reacted with an acid derivative as previously described gives the corresponding ester.

Compounds containing other B groups (ie aminomethyl, methylene or methyl groups) can be derived from formaldehyde and dimethylamine, diethylamine, piperidine or pyrrolidine from the products where A is = 0 and B is ═H ₂ . Obtained by the Mannich reaction using such secondary amines. This reaction yields the corresponding aminomethyl compound,
B is at the dimethylaminomethyl, upon removal of the amine moiety by heating 90-110 ° C. in an inert solvent such as toluene, corresponding methylene compound (B yields a = CH _2. The exo-cyclic methylene compound It can be isolated by standard methods and converted to a methyl group by hydrogenation using, for example, hydrogen and platinum oxide.

To obtain compounds where A is hydroxyimino (= N-OH), the above ketones can be reacted with hydroxylamine hydrochloride by standard procedures.

The alcohol used as a reactant in the above procedure is obtained from the known alkyl (C _1-4 ) ₃ -cyclopentene-1-carboxylates by a multi-step procedure. Specifically, N-methylmorpholine N-oxide in the presence of an osmium tetroxide catalyst is used to oxidize the double bond in the indicated cyclopentene to 1,2-diol. The diol is then cleaved to the corresponding dialdehyde using sodium metaperiodate. Robinson-Chef cyclization of dialdehydes with lower alkyl glycine esters and acetone dicarboxylic acid, preferably at pH 4, yields the following forms of pseudoperetieline derivatives.

The ketone group is reduced to the alcohol using sodium borohydride and the product is reacted with dihydropyran to protect the -OH group as the tetrahydropyranyl ether. Aqueous acid hydrolysis and decarboxylation following the Diekmann cyclization of the diester using a strong base (eg, potassium tert-butoxide) gives the desired alcohol. The resulting alcohol can exist in two configurations, axial and equatorial. The main product obtained in the above procedure is an axial alcohol, which can be separated from the equatorial isomer by cyclization of camphorsulphonate or tetrafluoroborate.

EFFECTS OF THE INVENTION The present compounds are useful for treating pain, particularly migraine, vascular and cluster headaches, and trigeminal neuralgia. They are also useful in the treatment of nausea and vomiting resulting from the treatment of cancer chemotherapeutic agents.

[Prior Art and Problems] In the past, acute attacks of migraine have been co-administered with caffeine, peripheral vasoconstrictors such as ergotamine and dihydroergotamine; hypothermic analgesics such as acetylsalicylic acid and p-acetylaminophenol; And / or have been treated with antiemetic agents such as cyclidine, metoclopramide and thiethylperazine. There was also a report that immediate relief of acute migraine attacks was obtained by slow intravenous injection of metoclopramide (10 mg) [JBHughes, Med.J.Aust. 17
No., p. 580, 1977].

5-Hydroxytryptamine (5-HT) is considered to be the natural substance most likely to play a role in the pathology of migraine. During most attacks, the amount of 5-HT and its metabolite 5-hydroxyindoleacetic acid excreted in urine is increased. In addition, plasma and platelet 5-HT concentrations fall sharply at the onset of seizures and remain low during headaches. And migraine attacks
Some patients were closely associated with the duration of thrombocytopenia. 5
It was pointed out that compounds that suppress the activity of HT are useful for symptomatic treatment of migraine [JRFozard, 1980 International Headache Conference, Advances i
n Neurology Volume 33, Raven Press, New York, 19
82 years].

The known migraine-preventing agents methysergide, propranolol, amitriptyline, and chlorpromazine have very different pharmacological activities, but they all have 5-HT D-receptor blockers at the doses clinically used to prevent migraine. It is an anti-drug. Metoclopramide is a potent 5-HT M-receptor antagonist and it was pointed out that blockade of M-receptors on afferent sensory neurons resulted in relief of acute migraine attacks [ [JR Fozard].

Pseudotropyl benzoate (ie benzoyl pseudotropin) as a 5-HT M-receptor antagonist and 3,
The potency of (−) cocaine and some related compounds, including 5-dichlorobenzoyltropine, was reported [J.
Earl Fozard et al., Eur.J.Pharmacol. 59 (1979)
1958-210; J. Fozard, Naunyn
-Schmiedeberg's Arch. Pharmacol. 326 (1984) 36
-44]. The pA ₂ values reported for motoclopramide, pseudotropyl benzoate, nor (−) cocaine and benzoyltropine were 7.2, 7.0, 7.7 and 7.2, respectively, while measured for 3,5-dichlorobenzoyltropine by the same procedure. The pA ₂ value obtained was 9.3 (Jar Fozard et al., Eur. J. Pharmacol. 49 (1978) 109-112; J Fozard,
Naunyn-Schmiedeberg's Arch. Pharmacol. 326 (1984
Year) 36-44]. In a double-blind clinical trial, 3,5-dichlorobenzoyltropin was shown to be an effective treatment for acute migraine attacks [C. Loisy et al., Cepha
lal-gia 5 (1985) pp. 79-82]. Furthermore, 5-HT M-
A series of Toro pins esters is between the pA ₂ values for blockade of receptors is 7.7 and 13.6 are, Richardson (Richardso
n) et al., Nature 316 (1985), pages 26-131.

Means for Solving the Problems The compounds of the present invention block the M-receptor for 5-hydroxytryptamine (5-HT) on afferent sensory neurons. Some of these neurons facilitate pain transmission. As explained above, such M-receptor blockade is believed to be a mechanism to reduce the symptoms of migraine. Thus, the compounds are useful in the treatment of migraine when administered in an amount sufficient to effectively block the M-receptor.

In addition, compounds that block the 5-HT M-receptor, including metoclopramide, 3,5-dichlorobenzoyltropine and (3α-tropanyl) -1H-indole-3-carboxylic acid ester were tested in animal studies. Very effective in preventing nausea and vomiting induced by cancer chemotherapeutic agents in a model (WDMiner)
Et al., Brit. J. Pharmacol., 88 (1986), p. 374; W. Dee Miner and GJSanger, Brit. J. Pharmacol., 88 (1986) 49.
7-499; B. Costall et al., Neuroph
armacology. 25 (1986) 959-961]. Vomiting induced by cytotoxic drugs is believed to involve the 5-HT M-receptor mechanism (W. D. Minor and G. J. Sanger, Brit. J. Pharmacol., 88.
Volume (1986) 497-499]. Therefore, the present compounds are M
-Useful in treating vomiting induced by cytotoxic drugs when administered in an amount sufficient to effectively block the receptor.

The activity of compounds against 5-HT is
Fozard et al., Eur. J. Pharmacol. 59: 195-210 (1979).
, And can be assessed by measuring pA ₂ in isolated rabbit hearts. In the method described, the molar concentration of the antagonist is determined such that the 2-fold ED ₅₀ effect of 5-HT is reduced to that of the ED ₅₀ in the absence of the antagonist. The pA ₂ value is logarithmically negative for this molar concentration. In general, the higher the pA ₂ value, the more potent the compound. When tested in this manner, the compounds generally have about 8
The pA ₂ values in the range of −10 are shown.

The activity of these compounds on 5-HT can be evaluated in vivo by inducing the von Betzold-Järish reflex with 5-HT injected intravenously in rats and measuring the effect of the compounds on this reflex [ Paintal
PA, Physiol. Rev. 53 Volume 159-227
Page (1973); AZ Fozard, Naunyn-
Schmiedeberg's Arch. Pharmacol. 326 (1984) 36-
See page 44]. Temporary decrease in pulsation is due to stimulation of afferent sensory fibers in and around the heart with 5-HT, and this stimulation enhances afferent vagal activity. The compound endo-8- (3,5-dimethylbenzoyloxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H) was tested when tested against the 5-HT-induced von Bézold-Jarish reflex. -One hydrochloride and endo-hexahydro-8- (3-indolylcarbonyloxy) -2,6-methano-2H-quinolidin-3 (4H) -one hydrochloride were administered 0.01-0.1 mg / kg or 0.25-1 mg / kg administered orally
Suppressed the response in a dose-dependent manner.

The compounds are highly selective in their action on the 5-HT M-receptor. Their efficacy against other 5-HT receptors and other convulsants, especially carbachol, phenylephrine, histamine and calcium, is
-It is known to be at least 3 orders of magnitude lower than for the receptors. Therefore, their use in treating migraine and vomiting induced by cytotoxic drugs should be without side effects.

The compounds can be administered in various ways to achieve the desired effect. The compounds can be administered orally or parenterally, eg, subcutaneously or intravenously, alone or in the form of a pharmaceutical preparation, to the treated patient. These can also be administered by inhalation or suppositories. The dosage of the compound can vary, and can be any migraine-reducing effective amount or amount effective for vomiting with a cytotoxic agent. Depending on the patient and the mode of administration, the dosage of compounds varies over a wide range to provide about 0.01 mg to about 10 mg per kg patient body weight per dose, usually 0.03 to 3.0 mg. The unit dose of these compounds is, for example, about 0.5 mg to 100 mg, usually 1 to 50 mg and preferably 3 to 3 mg.
It contains 0 mg of compound and can be administered, for example, 1-4 times daily.

The term "unit dose form" is used to mean a single or multiple dose form containing the quantity of active ingredient, mixed or combined with the filler or carrier, which quantity is One or more pre-determined units are in an amount as normally required for a single therapeutic administration. In the case of multiple dose forms such as liquid or incised tablets, the prescribed unit is a multiple dose, such as 5 ml (tea spoon) of liquid or half or a quarter of incised tablets. It is part of the format.

A particular formulation of the invention is itself made by methods well known in the pharmaceutical art and is usually mixed with, or otherwise combined with, a pharmaceutically acceptable carrier or filler, or at least one of them. It consists of two active compounds according to the invention. To make these formulations, the active ingredient is usually mixed with a carrier, diluted with a bulking agent, or enclosed or encapsulated in capsules, sachets, cachets, papers or other containers. The carrier or bulking agent may be a solid, semi-solid, or liquid material which acts as an excipient, auxiliary or vehicle for the active ingredient. Suitable carriers and bulking agents are known per se. See Remington Pharmaceutical Sciences (Mac Publishing, Easton, PA) for a description of the preparation of such formulations.

The formulations of the present invention can be adapted for enteral or parenteral administration and can be administered to patients in the form of tablets, capsules, suppositories, solutions, suspensions and the like.

The compounds of the present invention can be used in migraine therapy in combination with other anti-migraine agents with different modes of action. Such agents include prophylactic agents such as barbitalate, diazepam, chlorpromazine, amitriptyline, propanolol, methysergide, pizotiphene, cyproheptadine, dihydroergotamine, and clonidine; and vasoconstrictors such as ergotamine and dihydroergotamine, analgesic / anti-inflammatory agents such as Includes aspirin, paracetamol and indomethacin, or antiemetics such as those used for acute seizures such as cyclidine, metoclopramide and thiethylperazine [Fozard J.A.
Le, J.Pharm.Pharmacol., 27, 297-321 (1975);
Saper, JR, J.Amer.Me
d. Assoc. 239: 480-484 (1978); see Fozard J. R., supra]. As an example, the compounds of the present invention may be beneficially combined with a daily dose of 300-1200 mg aspirin or 2-6 mg methysergide.

Examples The following examples are presented to illustrate the invention, but they should not be construed as limiting the invention.

Example 1 (Preparation of the starting material) To a stirred solution of 160 g of diethyl malonate in 1.5 liters of dry dimethylformamide, 30 g of lithium hydride were slowly added under nitrogen at 0 ° C. After hydrogen evolution ceased (2 hours), cis-1,4-dichloro-2-butene was slowly added to allow the mixture to warm to room temperature. After 72 hours, the mixture was a mixture of ether and hexane (1: 4).
Diluted with and poured into water. The organic phase was washed with water and brine, then dried over magnesium sulfate. Upon distillation, 3-cyclopentene-1,1-containing a small amount (~ 10%) of diethyl 2-vinylcyclopropane-1,1-dicarboxylate.
This produced diethyl dicarboxylate (boiling point 70-80 ° C / 0.1 mm).

148.5 g of impure cyclopentene diester obtained above
Was added to a solution of 118 g of potassium hydroxide in 1333 ml of 80% ethanol and the stirred solution was warmed to 60-70 ° C overnight. The ethanol was evaporated and the residue was treated with an ice cold solution of 107 ml concentrated sulfuric acid in 274 ml water. The acid mixture was converted to ether (3 x 400 m
Extraction with l), followed by evaporation of the dried ether extract gave a residue of the diacid, which was heated in an oil bath at 170-180 ° C for 1 hour to decarboxylate to the monoacid. Distillation of the residual oil gave crude 3-cyclopentene-1-carboxylic acid (boiling point) containing some γ-vinyl-γ-butyrolactone.
68-73 ° C / 1 mm). 98g potassium carbonate in 300ml water
Was added and the mixture was extracted with ether to remove γ-vinyl-γ-butyrolactone. Acidification of the aqueous solution and extraction with ether yielded pure 3-cyclopentene-1-carboxylic acid.

Example 2 (Preparation of starting material) A mixture of 52 g of 3-cyclopentene-1-carboxylic acid and an excess of thionyl chloride was stirred at room temperature for 1 hour. Excess thionyl chloride was evaporated and the residue was distilled to give 3-cyclopentene-1-carbonyl chloride, bp 52-58 ° C,
Occurred.

The acid chloride obtained above was added slowly to a stirred ice-cold solution of 32 g of pyridine in 150 ml of ethanol. The mixture was stirred for another hour, the ethanol was evaporated and the residue was treated with water and ether. The ether layer was separated, washed several times with water and dried. Evaporation of the ether left a residue of ethyl 3-cyclopentene-1-carboxylate. Boiling point 62.5-66 ℃ / 14mm.

Example 3 (Preparation of starting material) A solution containing 84.6 g of N-methylmorpholine N-oxide, 1 g of osmium tetroxide, 230 ml of water, and 115 ml of acetone was stirred at room temperature for 30 minutes. In this agitated mixture,
A solution of 80 g of ethyl 3-cyclopentene-1-carboxylate in 115 ml of acetone was added very slowly over a period of at least 8 hours. The stirred mixture was heated at 50 ° C. for 2 hours to complete the reaction (ethyl acetate / hexane 70).
Confirmed by TLC test using / 30). Sodium bisulfite (~ 10g) was added, stirring was continued for another 15 minutes and the mixture was filtered through Celite. The pH of the filtrate was 37 ml of 12N sulfuric acid.
Was adjusted to 7 by addition of, the residual solution pH was adjusted to 2 with 13 ml of 12N sulfuric acid and the solution was extracted with ethyl acetate (4 × 250 ml). Evaporation of the dry ethyl acetate solution yielded 4-ethoxycarbonyl-1,2-cyclopentanediol.

Example 4 (Preparation of starting material) A solution of 85.4 g of sodium periodate in 500 ml of water is treated with 4-ethoxycarbonyl- in 690 ml of tetrahydrofuran.
69 g of 1,2-cyclopentanediol was slowly added to the stirred solution. The reaction was exothermic and required cooling. After 2 hours, the sodium iodide precipitate was filtered off and the solution was concentrated at room temperature to remove most of the tetrahydrofuran. The resulting aqueous solution contained the desired β-ethoxycarbonylglutaraldehyde and was used directly in the next reaction.

To a stirred suspension of 400 g of potassium hydrogen phthalate in 800 ml of water, a solution of 80 g of acetonedicarboxylic acid in 1200 ml of water, a solution of 80 g of glycine ethyl ester hydrochloride in 400 ml of water, and finally the β obtained above. -Ethoxycarbonylglutaraldehyde solution was added one after another. The mixture was stirred at room temperature for 20 hours, during which time carbon dioxide evolved. The mixture was made basic by the addition of an excess of aqueous potassium carbonate solution and extracted several times with ethyl acetate. Evaporation of the dry ethyl acetate extract gave mainly 7-ethoxycarbonyl-9-.
(Ethoxycarbonylmethyl) -9-azabicyclo [3.
3.1] A syrup consisting of nonan-3-one was produced.

Example 5 (Preparation of starting material) 7-Ethoxycarbonyl-9- in 750 ml of ethanol
(Ethoxycarbonylmethyl) -9-azabicyclo [3.
3.1] Nonan-3-one 177.6 g of sodium borohydride was added little by little to a stirred solution of 87.6 g. The mixture was stirred at room temperature overnight, the ethanol was evaporated and the residue was washed with water.
Treated with 0 ml. Hydrochloric acid (2M) was added until the mixture was acidic and the acid solution was immediately made basic by the addition of saturated potassium carbonate solution. Extraction with ethyl acetate and evaporation of the dried extract gave mainly 7-ethoxycarbonyl-9-.
(Ethoxycarbonylmethyl) -9-azabicyclo [3.
3.1] A syrup consisting of nonan-3-ol was produced.
The syrup can be purified by column chromatography using silica and elution with hexane-ethyl acetate (30:70).

Example 6 (Preparation of starting material) A solution of 26.1 g of crude 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl) -9-azabicyclo [3.3.1.] Nonan-3-ol in 250 ml of methylene chloride was added to 1 equivalent of methane. Treated with 8.42 g of sulfonic acid. The methylene chloride solution was concentrated to about 35 ml, 9.5 ml of dihydropyran was added along with 1 drop of methanesulfonic acid and the mixture was stirred at room temperature for 3 hours. Then the mixture was poured into saturated potassium carbonate solution and the product was isolated by ethyl acetate extraction.

Evaporation of the dry ethyl acetate extract yielded a syrup consisting mainly of the tetrahydropyranyl ether of 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl) -9-azabicyclo [3.3.1] nonan-3-ol. It can be purified by column chromatography using silica and hexane-ethyl acetate (20:80), Rf 0.7.

Example 7 (Preparation of starting material) 7-Ethoxycarbonyl-9 in 800 ml of anhydrous toluene
A solution of 34 g of tetrahydropyranyl ether of-(ethoxycarbonylmethyl) -9-azabicyclo [3.3.1] nonan-3-ol was treated with 19 g of potassium tert-butoxide and the stirred mixture was heated at 100 ° C for 2 hours. 7.85 g of formic anhydride was added to the cooled mixture, potassium formate was filtered off and the toluene solution was evaporated to give a syrup. The syrup was treated with 300 ml of 5N hydrochloric acid and the stirred solution was refluxed overnight. The cooled mixture was purified by methylene chloride extraction and the aqueous acid solution was evaporated to dryness. The residue was dissolved in a small amount of water and the solution was treated with a large excess of saturated potassium carbonate solution. The resulting mixture was extracted with ethyl acetate and the dry ethyl acetate solution was evaporated to give endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizine-3.
The (4H) -one occurred as an oil which crystallized on standing. The base was converted to its camphor sulphonate using 1 equivalent of camphor sulphonic acid in ethanol. Melting point 178
° C.

Example 1 A mixture of 1.8 g of endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one, borohydrofluoric acid (0.88 g; 60% aqueous solution), and 20 ml of ethanol was evaporated. And treat the residue with 50 ml of anhydrous toluene,
The mixture was evaporated again. A stirred suspension of the anhydrous residue in 50 ml of anhydrous nitroethane was treated with 1.94 g of anhydrous silver tetrafluoroborate at -78 ° C and a solution of 1.7 g of 3,5-dimethylbenzoyl chloride in 20 ml of anhydrous nitroethane was slowly added. Was added. The temperature of the stirred reaction was held at -78 ° C for 1.5 hours and then allowed to come to room temperature overnight. 1 g of triethylamine was added, the solution was filtered and the nitroethane was evaporated. Water 20
A solution of the residue in ml was treated with an excess of saturated aqueous potassium carbonate solution and the oil released was separated by ethyl acetate extraction.
The ethyl acetate solution was washed several times with water, then dried over magnesium sulfate and evaporated. The resulting residue is endo-8-
(3,5-Dimethylbenzoyloxy) hexahydro-2,6-
It was methano-2H-quinolizin-3 (4H) -one, which was treated with methylene chloride and ethereal hydrogen chloride to give hydrochloride crystals with a melting point of about 291 ° C.

Example 2 Using the endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one and the appropriate acid chloride, the procedure of Example 1 was repeated to give: The corresponding esters listed are obtained. If desired, the acid chloride can be prepared by standard procedures, for example using thionyl chloride,
Obtained from the appropriate carboxylic acid. To convert the ester to the corresponding acid salt, an alternative solvent is optionally used,
The ester was reacted with the appropriate acid.

Endo-hexahydro-8- (3-indolylcarbonyloxy) -2,6-methano-2H-quinolizine-3 (4H)
-One methanesulfonate, melting point about 278 ° C, endo-8- (3-benzofurancarbonyloxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H)
-One, endo-8- (3-benzo [b] thiophene carbonyloxy) hexahydro-2,6-methano-2H-quinolidin-3 (4H) -one, endo-8- (1-benzyl-1H-indole -3-
Ilcarbonyloxy) hexahydro-2,6-methano-2H
-Quinolidin-3 (4H) -one, endo-hexahydro-8- (1-methyl-1H-indol-3-ylcarbonyloxy) -2,6-methano-2H
-Quinolizin-3 (4H) -one, endo-8- (4-bromo-2-furylcarbonyloxy) hexahydro-2,6-methano-2H-quinolizine-3
(4H) -one, endo-hexahydro-8- (5-phenyl-2-furylcarbonyloxy) -2,6-methano-2H-quinolidin-3 (4H) -one, endo-8- (3-chloro -2-thienylcarbonyloxy) hexahydro-2,6-methano-2H-quinolizine-
3 (4H) -one, endo-hexahydro-8- (5-methyl-2-thienylcarbonyloxy) -2,6-methano-2H-quinolidin-3 (4H) -one, endo-hexahydro-8- ( 1-Methyl-1H-pyrrol-2-ylcarbonyloxy) -2,6-methano-2H-
Quinolidin-3 (4H) -one, endo-8- (3-chloro-4-nitrobenzoyloxy) hexahydro-2,6-methano-2H-quinolidin-3
(4H) -one, endo-8- (3-chloro-4-dimethylaminobenzoyloxy) hexahydro-2,6-methano-2H-quinolidin-3 (4H) -one, endo-8- (3,5 -Dichlorobenzoyloxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H)-
On, endo-8- (3,5-dimethoxybenzoyloxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H)
-One, endo-8- (2,5-dimethylbenzoxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H)-
on.

Example 3 1 g of 5-methylindole in 20 ml of anhydrous ether at 0 ° C
0.76 ml of oxalyl chloride was gradually added to the stirred solution. The precipitate formed is filtered off and dried at 80 ° C,
This produced 5-methyl-3-indolylglyoxylyl chloride.

A solution of 205 mg of anhydrous silver tetrafluoroborate in 10 ml of anhydrous nitroethane was stirred at room temperature to give anhydrous nitroethane-1.
Endo-hexahydro-8-hydroxy-2,6-in 0 ml
It was treated with a solution of 282.5 mg of methano-2H-quinolidin-3 (4H) -one tetrafluoroborate (obtained by treating the free amine with 1 equivalent of borofluoric acid). A solution of 233 mg of 5-methyl-3-indolylglyoxylyl chloride chloride in 10 ml of anhydrous nitroethane was added slowly and the mixture was stirred overnight at room temperature. 101 mg of triethylamine was added, and the mixture was stirred with the solution. 101 mg triethylamine were added, the solution was filtered and the nitroethane was evaporated. A solution of the residue in 15 ml of water was treated with saturated aqueous potassium carbonate solution and the released oil was separated by ethyl acetate extraction. The ethyl acetate solution was washed several times with water, then dried over magnesium sulfate and evaporated. The residue was treated with methylene chloride and ethereal hydrogen chloride, the solid was filtered off and recrystallized from 2-propanol to give endo-hexahydro-8- (5-methyl-3-.
This yielded indolylcarbonyloxy) -2,6-methano-2H-quinolidin-3 (4H) -one hydrochloride.

The above procedure was repeated using the appropriate substituted indole instead of 5-methylindole to give the following compounds.

Endo-hexahydro-8- (5-chloro-3-indolylcarbonyloxy) -2,6-methano-2H-quinolidin-3 (4H) -one hydrochloride, after recrystallization from ethanol,
Melting point about 317-320 ° C (decomposition), endo-hexahydro-8- (5-cyano-3-indolylcarbonyloxy) -2,6-methano-2H-quinolizin-3 (4H) -one hydrochloride, ethanol After recrystallization from
Melting point about 304-305 ° C (decomposition), endo-hexahydro-8- (5-methoxy-3-indolylcarbonyloxy) -2,6-methano-2H-quinolidin-3 (4H) -one hydrochloride, isopropanol After recrystallization from, melting point approx. 303 ° C (decomposition).

Also, endo-hexahydro-8- (5-carbamoyl-3-indolylcarbonyloxy) -2,6-methano-2
H-quinolizin-3 (4H) -one and endo-hexahydro-8- (5-hydroxy-3-indolylcarbonyloxy) -2,6-methano-2H-quinolizine-3 (4H)-
ON can be obtained similarly. In the latter case, the starting material is 5-benzyloxyindole and the initial product is debenzylated by reduction using standard procedures.

Example 4 Dimethylamine (40% aqueous solution, 0.68 g) and formaldehyde (30% aqueous solution, 0.49 g) were added to ethanol (4 ml) and water (2 m).
One after another was added to a solution of 1.25 g of endo-8- (3,5-dimethylbenzoyloxy) hexahydro-2,6-methano-2H-quinolizin-3 (4H) -one in a mixture with l. The stirred mixture was heated to 70-75 ° C for 16 hours and concentrated. 50 ml of toluene were added and the mixture was evaporated at 110.degree.

Residue in 30 ml of ethanol [endo-8- (3,5-dimethylbenzoyloxy) hexahydro-4-methylene-
A solution of 2,6-methano-2H-quinolidin-3 (4H) -one] was hydrogenated at room temperature and atmospheric pressure in the presence of 0.2 g of platinum oxide (Adams catalyst). One equivalent of hydrogen was absorbed in one hour. The catalyst was filtered off, the ethanol was evaporated and the residue was treated with 1 equivalent of aqueous borofluoric acid solution. Evaporation of the aqueous solution yielded a crystalline residue, which upon recrystallisation from ethanol had an end-8 of mp.
-(3,5-Dimethylbenzoyloxy) hexahydro-4
-Methyl-2,6-methano-2H-quinolizine-3 (4H)-
This gave on-tetrafluoroborate.

Example 5 A solution of 1.42 g of endo-8- (3-indolylcarbonyloxy) hexahydro-2,6-methano-2H-quinolidin-3 (4H) -one in 5 ml of ethanol was treated with fluoroboric acid (0.64 g, 60 % Aqueous solution) and the mixture was evaporated to give endo-8- (3-indolylcarbonyloxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H)-.
This gave 1.8 g of ontetrafluoroborate.

A stirred suspension of 1.8 g of the above salt in 30 ml of anhydrous nitroethane was treated with 3 ml of propane-1,3-dithiol and boron trifluoride ether compound (3 drops) and the mixture was stirred overnight at room temperature. The nitroethane was removed by evaporation and the residue was triturated with ether. The solid product was filtered off, washed several times with ether and treated with 25 ml water, 3 ml saturated aqueous potassium carbonate solution and 50 ml ether. The ether solution was separated and dried with (MgSO ₄₎ evaporated to give the propane dithioketal derivative. Melting point 226-229 ° C (1.6g).

To a stirred refluxing solution of 0.5 g of the above dithioketal in 20 ml of isopropanol was added dropwise 3 ml of hydrazine hydrate in the presence of Raney nickel (6 g, previously washed 3 times with isopropanol). 3 more reflux
After holding for 0 minutes, the hot solution was filtered through triple superphosphate, the nickel was washed several times with hot isopropanol and the combined filtrates were evaporated to give End-8-
(3-Indolylcarbonyloxy) -2,6-methanooctahydro-2H-quinolidine yielded 50 mg of free base. The addition of methylene chloride and ethereal hydrogen chloride is
g) occurred. Melting point 311-313 [deg.] C (from ethanol).

Example 6 The procedure of Example 5 was repeated using endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolidin-3 (4H) -one in place of the ester. The resulting dithioketal was reduced as described in the previous section, but leaving hydrazine hydrate. This gives exo-octahydro-2,6-methano-2H-quinolizin-8-ol, which is then reacted with 3,5-dimethylbenzoyl chloride to give exo-8- (3,5-dimethylbenzoyl Roxy) octahydro-2,6-methano-2H-quinolidine, which was converted to the hydrochloride salt by standard procedures. Melting point
255-256 ° C.

Claims (14)

(57) [Claims] 1. A formula [Wherein A has the formula _{= H 2, = O, =} (H) (OH) or = a N-OH, B is _{= H 2, = (H)} (CH3), = (H) (CH 2 NR 3 R
₄₎ or = is CH _2, wherein R ₃ and R ₄ are either C _2-4 alkyl, or when taken together tetramethylene, pentamethylene or _{-CH 2 CH 2 -O-CH 2} CH 2 Yields − and R ₁ Wherein Z is NR ₉ , O or S, and R ₅ , R ₆ and R ₈ are hydrogen, halogen, C _1-3 alkyl or C _1-3 , respectively.
Alkoxy, R ₇ is hydrogen, amino, (C _1-4 alkyl) amino, (C _1-4 alkyl) ₂ amino or nitro, R ₉ is hydrogen, C _1-4 alkyl or phenyl (C _{1- 2} alkyl) and R ₁₀ is hydrogen, halogen, C _1-4 alkyl, C
_1-4 alkoxy, hydroxy, cyano, or -CONH ₂ , R ₁₁ is hydrogen, halogen, C _1-4 alkyl or phenyl, and the wavy line indicates that the configuration of the oxygen substituent on the ring is endo or exo. Or a pharmaceutically acceptable acid addition salt and quaternary ammonium salt of the above compounds. 2. A formula [Wherein A has the formula _{= H 2, = O, =} (H) (OH) or = a N-OH, B is _{= H 2, = (H)} (CH3), = (H) (CH 2 NR 3 R
₄₎ or = is CH _2, wherein R ₃ and R ₄ are either C _2-4 alkyl, or when taken together tetramethylene, pentamethylene or _{-CH 2 CH 2 -O-CH 2} CH 2 Yields − and R ₁ Wherein Z is NR ₉ , O or S, and R ₅ , R ₆ and R ₈ are hydrogen, halogen, C _1-3 alkyl or C _1-3 , respectively.
Alkoxy, R ₇ is hydrogen, amino, (C _1-4 alkyl) amino, (C _1-4 alkyl) ₂ amino or nitro, R ₉ is hydrogen, C _1-4 alkyl or phenyl (C _{1- 2} alkyl) and R ₁₀ is hydrogen, halogen, C _1-4 alkyl, C
_1-4 alkoxy, hydroxy, cyano, or -CONH ₂ and R ₁₁ is hydrogen, halogen, C _1-4 alkyl or phenyl]. Pharmaceutically acceptable acid addition salts and quaternary ammonium salts thereof. 3. A formula [Wherein A is = H ₂ , = O, = (H) (OH), or = N-OH
And R ₁ is Wherein Z is NR ₉ , O or S, and R ₅ , R ₆ and R ₈ are hydrogen, halogen, C _1-3 alkyl or C _1-3 , respectively.
Alkoxy, R ₇ is hydrogen, amino, (C _1-4 alkyl) amino, (C _1-4 alkyl) ₂ amino or nitro, R ₉ is hydrogen, C _1-4 alkyl or phenyl (C _{1- 2} alkyl) and R ₁₀ is hydrogen, halogen, C _1-4 alkyl, C
_1-4 alkoxy, hydroxy, cyano, or -CONH ₂ and R ₁₁ is hydrogen, halogen, C _1-4 alkyl or phenyl]. Pharmaceutically acceptable acid addition salts and quaternary ammonium salts thereof. 4. A formula [Where R ₁ is Wherein Z is NR ₉ , O or S, and R ₅ , R ₆ and R ₈ are hydrogen, halogen, C _1-3 alkyl or C _1-3 , respectively.
Alkoxy, R ₇ is hydrogen, amino, (C _1-4 alkyl) amino, (C _1-4 alkyl) ₂ amino or nitro, R ₉ is hydrogen, C _1-4 alkyl or phenyl (C _{1- 2} alkyl) and R ₁₀ is hydrogen, halogen, C _1-4 alkyl, C
_1-4 alkoxy, hydroxy, cyano, or -CONH ₂ and R ₁₁ is hydrogen, halogen, C _1-4 alkyl or phenyl]. Pharmaceutically acceptable acid addition salts and quaternary ammonium salts thereof. 5. A formula [Where R ₁ is Wherein Z is NR ₉ , O or S, and R ₅ , R ₆ and R ₈ are hydrogen, halogen, C _1-3 alkyl or C _1-3 , respectively.
Alkoxy, R ₇ is hydrogen, amino, (C _1-4 alkyl) amino, (C _1-4 alkyl) ₂ amino or nitro, R ₉ is hydrogen, C _1-4 alkyl or phenyl (C _{1- 2} alkyl) and R ₁₀ is hydrogen, halogen, C _1-4 alkyl, C
_1-4 alkoxy, hydroxy, cyano, or with -CONH ₂ is], the compounds according to paragraph 1 the claims, or a pharmaceutically acid addition salts and quaternary ammonium salts to be received of the compounds. 6. End-8- (3,5-dimethylbenzoxy) hexahydro-2,6-methano-2H-quinolizine-
A compound according to claim 1 which is 3 (4H) -one. 7. End-8- (3-indolylcarbonyloxy) hexahydro-2,6-methano-2H-quinolizine-
A compound according to claim 1 which is 3 (4H) -one. 8. A formula [Wherein A has the formula _{= H 2, = O, =} (H) (OH) or = a N-OH, B is _{= H 2, = (H)} (CH3), = (H) (CH 2 NR 3 R
₄₎ or = is CH _2, wherein R ₃ and R ₄ are either C _2-4 alkyl, or when taken together tetramethylene, pentamethylene or _{-CH 2 CH 2 -O-CH 2} CH 2 Yields − and R ₁ Wherein Z is NR ₉ , O or S, and R ₅ , R ₆ and R ₈ are hydrogen, halogen, C _1-3 alkyl or C _1-3 , respectively.
Alkoxy, R ₇ is hydrogen, amino, (C _1-4 alkyl) amino, (C _1-4 alkyl) ₂ amino or nitro, R ₉ is hydrogen, C _1-4 alkyl or phenyl (C _{1- 2} alkyl) and R ₁₀ is hydrogen, halogen, C _1-4 alkyl, C
_1-4 alkoxy, hydroxy, cyano, or -CONH ₂ , R ₁₁ is hydrogen, halogen, C _1-4 alkyl or phenyl, and the wavy line indicates that the configuration of the oxygen substituent on the ring is endo or exo. Or a pharmaceutically acceptable acid addition salt thereof and a quaternary ammonium salt of the above compound, wherein Alcohol or reactive derivative thereof with [A 'is = H ₂ or = O wherein, wherein R ₁ COOH [wherein R ₁ is as defined above] and their equivalents reactive with acid Reacting to obtain compounds where A is = H ₂ or = O, followed by optionally reducing (a) the product ketone with an alkali metal borohydride to provide A == (H) Make a compound for (OH),
Or (b) conversion of the product ketone to a dithioketal with ethylenedithiol or trimethylenedithiol followed by reduction with hydrazine in the presence of Raney nickel to form a compound where A is = H ₂ , or (c) formation The product ketone is reacted with hydroxylamine hydrochloride to form a compound where A is = N-OH, or (d) the product ketone is reacted with formaldehyde and a suitable secondary amine, B = (H) (CH ₂ NR ₃ R ₄ ) in the case of B, then when B is dimethylaminomethyl, it is heated to form a compound in the case of B = CH ₂ , and then by hydrogenation to B Is = (H) (CH ₃ )
In the case of the method consisting of making a compound. 9. Formula [Wherein A'is = H ₂ or = O and R ₁ is Wherein Z is NR ₉ , O or S, and R ₅ , R ₆ and R ₈ are hydrogen, halogen, C _1-3 alkyl or C _1-3 , respectively.
Alkoxy, R ₇ is hydrogen, amino, (C _1-4 alkyl) amino, (C _1-4 alkyl) ₂ amino or nitro, R ₉ is hydrogen, C _1-4 alkyl or phenyl (C _{1- 2} alkyl) and R ₁₀ is hydrogen, halogen, C _1-4 alkyl, C
_1-4 alkoxy, hydroxy, cyano, or -CONH ₂ and R ₁₁ is hydrogen, halogen, C _1-4 alkyl or phenyl], or a pharmaceutically acceptable acid addition salt of the above compounds. And a quaternary ammonium salt, wherein An alcohol or reactive derivative thereof having [where A ′ is as defined above] is equivalently reactive with an acid of the formula R ₁ COOH [wherein R ₁ is as defined above]. Claim 8 comprising reacting
Method by paragraph. 10. A formula [Wherein A'is = H ₂ or = O and R ₁ is Wherein R ₅ , R ₆ and R ₈ are each hydrogen, halogen, C _1-3 alkyl or C _1-3 alkoxy, and R ₇ is hydrogen, amino, (C _1-4 alkyl) amino, (C _1-4 alkyl) ₂ amino or nitro, R ₁₀ is hydrogen, halogen,
C _1-4 alkyl, C _1-4 alkoxy, hydroxy, cyano,
Or -CONH ₂ , R ₁₁ is hydrogen, halogen, C _1-4 alkyl or phenyl, Z is NR ₉ , O or S, R ₉
Is hydrogen, C _1-4 alkyl or phenyl (C _1-2 alkyl)], or a pharmaceutically acceptable acid addition salt and quaternary ammonium salt of the above compounds, formula Consisting of reacting an alcohol of the formula A'as defined above with an acid of the formula R ₁ COOH, wherein R ₁ is as defined above, the alcohol being a superacid of the alcohol. Used in the form of a salt in the presence of a heavy metal salt of the same superacid, this acid used in the form of the corresponding acid chloride or bromide or the corresponding chloride or glyoxyl bromide, the reaction in a nitroparaffin solvent, A method according to claim 8 carried out at a temperature between -80 ° C and ambient temperature for a period of up to about 24 hours. 11. An expression [Where R ₁ is Wherein Z is NR ₉ , O or S, and R ₅ , R ₆ and R ₈ are hydrogen, halogen, C _1-3 alkyl or C _1-3 , respectively.
Alkoxy, R ₇ is hydrogen, amino, (C _1-4 alkyl) amino, (C _1-4 alkyl) ₂ amino or nitro, R ₉ is hydrogen, C _1-4 alkyl or phenyl (C _{1- 2} alkyl) and R ₁₀ is hydrogen, halogen, C _1-4 alkyl, C
_1-4 alkoxy, hydroxy, cyano, or -CONH ₂ and R ₁₁ is hydrogen, halogen, C _1-4 alkyl or phenyl], or a pharmaceutically acceptable acid addition salt of the above compounds. And a quaternary ammonium salt, wherein Reacting an alcohol with an acid of the formula R ₁ COOH, where R ₁ is as defined above, wherein the alcohol is in the form of the alcohol's superacid salt, in an equivalent amount of a heavy metal of the same superacid. Used in the presence of salt,
This acid is used in the form of the corresponding acid chloride or bromide or the corresponding glyoxyl chloride or bromide and the reaction is carried out in a nitroparaffin solvent at a temperature between −80 ° C. and ambient temperature, about.
A method according to claim 8 carried out for a period of up to 24 hours. 12. A formula [Where R ₁ is Wherein Z is NR ₉ , O or S, and R ₅ , R ₆ and R ₈ are hydrogen, halogen, C _1-3 alkyl or C _1-3 , respectively.
Alkoxy, R ₇ is hydrogen, amino, (C _1-4 alkyl) amino, (C _1-4 alkyl) ₂ amino or nitro, R ₉ is hydrogen, C _1-4 alkyl or phenyl (C _{1- 2} alkyl) and R ₁₀ is hydrogen, halogen, C _1-4 alkyl, C
_1-4 alkoxy, hydroxy, cyano, or -CONH ₂ ], or a pharmaceutically acceptable acid addition salt and quaternary ammonium salt of the above compounds, wherein Of an alcohol of formula R ₁ COOH, wherein R ₁ is as defined above, wherein the alcohol is in the form of a superacid salt of the alcohol, in an equivalent amount of a heavy metal of the same superacid. Used in the presence of salt,
This acid is used in the form of the corresponding acid chloride or bromide or the corresponding glyoxyl chloride or bromide and the reaction is carried out in a nitroparaffin solvent at a temperature between -80 ° C and ambient temperature of about 24 ° C.
A method according to claim 8 carried out for a period up to an hour. 13. Endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one, first with borofluoric acid, then with silver tetrafluoroborate, and finally with chloride. End-8 according to claim 9 comprising reacting with 3,5-dimethylbenzoyl.
-(3,5-Dimethylbenzoyloxy) hexahydro-2,6
-Methano-2H-quinolizin-3 (4H) -one production method. 14. Endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one first of all, borofluoric acid first, then silver tetrafluoroborate and finally indole. Endo-8- (3-indolylcarbonyloxy) hexahydro-2,6-methano-2H-quinolizine-3 (4H) according to claim 8 comprising reacting with -3-carboxylic acid chloride. ) -On manufacturing method.